The Oral Microbiome and Upper Aerodigestive Squamous Cell Cancer We propose an innovative study to examine whether the oral microbiome is associated with risk of upper aerodigestive squamous cell cancers (UADSCC: oral, pharyngeal, laryngeal and esophageal squamous cell cancers). Our research team has developed a unique capability to conduct microbiome research (NIH grant: 1UH2CA140233, 5R01AI063477), have recently reported the relationship of foregut microbiome profiles with esophageal premalignant conditions (Yang et al., Gastroenterology, 2009), and now have preliminary data showing an association between the oral microbiome and oral cancer risk. Tobacco and alcohol are the major known risk factors for UADSCC. We hypothesize that microorganisms in the oral cavity potentiate UADSC carcinogenesis, potentially related to alcohol and tobacco use. The goals of our study are to relate the oral microbiome to UADSCC risk and to identify the impact of alcohol and tobacco use on the oral microbiome, in the first epidemiologic investigation of this topic. We plan to characterize, in 140 UADSCC cases and 420 controls, all common oral microbial species (including non-culturables) by sequencing the 16S rRNA microbial genes in oral wash samples. Because UADSCC disease and treatment status can alter oral microbial profiles (reverse causation), we are using a prospective research design, in the ACS and PLCO cohorts in which oral wash samples were collected prior to disease development. Our study will identifying oral bacterial profiles related to UADSCC risk, providing direct leads to implement prophylactic interventions as critical adjuncts to alcohol and tobacco control programs in UADSCC prevention.